Journal of Ethnopharmacology 279 (2021) 114342

Available online 19 June 2021

A systematic review with meta-analysis on the antihypertensive efficacy of

Nigerian medicinal plants

Mansurah A. Abdulazeez ^a, Suleiman Alhaji Muhammad ^b^,^*, Yusuf Saidu ^b, Abdullahi B. Sallau ^c,

Auwalu A. Arzai ^d, Musa Abdulkadir Tabari ^e, Abubakar Hafiz ^f, Muhammad Yalwa Gwarzo ^g,

Jiradej Manosroi ^h, Aminu Idi ^f, Musa Bashir ⁱ, Shamsudeen L. Pedro ^a

a Centre for Biotechnology Research, Bayero University, Kano, Nigeria

b Department of Biochemistry, Usmanu Danfodiyo University Sokoto, Nigeria

c Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria

d Department of Microbiology, Faculty of Science, Bayero University, Kano, Nigeria

e Department of Radiology, Barau Dikko Teaching Hospital (BDTH), Kaduna State University (KASU), Kaduna, Nigeria

f Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University, Kano, Nigeria

g Department of Medical Laboratory Science, Faculty of Allied Health Sciences, College of Health Sciences, Bayero University, Kano, Nigeria

h Department of Cosmetic Technology, Faculty of Engineering, North-Chiang Mai University, Chiang Mai, Thailand

i Centre for Dryland Agriculture, Bayero University, Kano, Nigeria

A R T I C L E I N F O

Keywords:

Nigerian medicinal plants

Hypertension

Systolic and diastolic pressure

Preclinical studies

Clinical trials

A B S T R A C T

Ethnopharmacological relevance: Despite the promising effects of herbal preparations in lowering blood pressure

(BP), hypertension remains a major clinical challenge in Nigeria. The BP-lowering effects of medicinal plants are

due to the presence of bioactive compounds.

Aim of the study: This meta-analysis presents a precise estimate of the therapeutic benefits of medicinal plants

utilized in Nigeria for the management of hypertension in animals and humans.

Methods: A systematic literature search was performed through Cochrane, PubMed, Science Direct and Scopus

databases from inception until February 28, 2021 using search terms related to randomized controlled trials of

Nigerian medicinal plants for hypertension. Additional studies were identified through manual search. BP was

the main outcome that was measured after the intervention. Meta-analysis was performed using the Review

Manager and Meta-Essential.

Results: Nineteen trials comprising of 16 preclinical and 3 clinical studies were enrolled for the meta-analysis. A

total number of 16 plants was identified of which H. sabdariffa was the highest reported plant. The plant extracts

significantly lowered the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the hypertensive

subjects compared to control. Weighted mean difference (WMD) for SBP (−43.60 mmHg, 95% CI: −63.18,

−24.01; p<0.0001) and DBP (-29.50 mmHg, 95 CI: −43.66, −15.34; p<0.0001) was observed for the preclinical

studies. For clinical trials, the WMD was −13.98 mmHg, 95 CI: −19.08, −8.88; p<0.00001 for SBP and −10.00

mmHg, 95 CI: −12.22, −7.78; p<0.00001 for DBP. High heterogeneity was observed for the outcome measures

of preclinical studies, but not for the clinical studies. The observed substantial heterogeneity in preclinical studies

may be linked to methodological shortcomings as evidenced by the results of the risk of bias assessment. There

was no evidence of publication bias in animal trials for BP using the funnel plot and Egger’s regression test (SBP,

p=0.239 and DBP, p=0.112).

Conclusions: This study provides evidence of medicinal preparations for the treatment of hypertension. A well-

conducted trial with methodological rigour and a longer duration of follow-up is required for their effective

clinical utilization.

Abbreviations: BP, blood pressure; CPT, cold pressor test; DBP, diastolic blood pressure; DF, diet formulation; DM, diabetes mellitus; DOCA, deoxycorticosterone

acetate; HGE, handgrip exercise; L-NAME, N-nitro-L-arginine methyl ester; MeOH, methanol; MD, mean difference; NO, nitric oxide; OS, oxidative stress; ROS,

reactive oxygen species; SD, standard deviation; SEM, standard error of the mean; SHR, spontaneously hypertensive rat; SBP, systolic blood pressure; WMD, weighted

mean difference.

* Corresponding author.

E-mail addresses: suleiman.muhammad@udusok.edu.ng, smbinna98@gmail.com (S.A. Muhammad).

Contents lists available at ScienceDirect

Journal of Ethnopharmacology

journal homepage: www.elsevier.com/locate/jethpharm

https://doi.org/10.1016/j.jep.2021.114342

Received 9 March 2021; Received in revised form 16 April 2021; Accepted 14 June 2021

Journal of Ethnopharmacology 279 (2021) 114342

1. Introduction

Hypertension is a chronic disease that is a risk factor for cardiovas-

cular and cerebrovascular diseases, resulting in clinical complications

such as stroke, heart failure, metabolic syndrome and renal dysfunction

(Bilbis et al., 2012; Muhammad et al., 2012; Shi et al., 2019). Obesity,

physical inactivity, smoking and high salt intake are the various pre-

disposing factors that have been implicated in the pathophysiology of

hypertension. Current evidence suggests that there is a connection be-

tween hypertension and continued endothelial damage. Endothelial

dysfunction is the inability of the endothelium to control vascular ho-

meostasis that can lead to a functional imbalance in favour of vaso-

constriction, pro-thrombosis and inflammation. The consequential effect

of which could lead to cardiovascular diseases and complications

(Roberts and Porter, 2013). Oxidative stress (OS) which is due to the

excess generation of reactive oxygen species (ROS) and inflammation

are the various mechanistic ways that have been implicated in the

development of hypertension (Muhammad et al., 2012; Rodrigo et al.,

2011). ROS is capable of diminishing nitric oxide bioavailability, a

factor that plays a significant role in maintaining healthy endothelium.

Therefore, treatment strategies targeting these factors could play

important roles in combating complications of hypertension.

The results of our previous study support the hypothesis linking

oxidative stress to hypertension (Saidu et al., 2012). In this study,

formulated antioxidant-rich nutraceutical from plant sources decreased

OS, increased NO bioavailability and improved the antioxidant status of

hypertensive rats, leading to a significant reduction in blood pressure.

This shows that plants could be explored as natural sources of bioactive

compounds for the treatment of hypertension. Furthermore, these plants

have been harnessed and are continually being explored for the devel-

opment of pharmaceutical drugs. It is, therefore, important that research

into the efficacy of these medicinal plants would help developing

countries, including Nigeria to develop new and safer medicinal rem-

edies for hypertension and other chronic diseases.

Consistent with this observation, several studies have reported me-

dicinal herbs as therapeutics for various diseases, including hyperten-

sion (Isari et al., 2019; Kim et al., 2018). Nigeria is not left out as studies

have indicated that medicinal plants are rich sources of natural bioactive

substances for the treatment of diseases (Gbolade, 2012; Salihu Shinkafi

et al., 2015). Despite the use of herbs as an alternative to conventional

drugs for the treatment and management of hypertension, the disease is

still a major health challenge in Nigeria. Medicinal plants have played a

significant role in the survival benefits of hypertensive patients due to

the inherent bioactive phytochemicals such as flavonoids, phenolics,

minerals and vitamins that are capable of exerting therapeutic and

curative effects. However, reports on meta-analysis of the efficacy of

Nigerian medicinal plants for the treatment of hypertension are scarce.

In this systematic review and meta-analysis, we investigated the anti-

hypertensive efficacy of Nigerian medicinal plants, with a view of

identifying the most used plant(s), their safety and the quality of the

studies that reported the use of these plants. This study included clinical

trials as well as preclinical studies that utilized plants from Nigeria for

the treatment of hypertension.

1.1. Review questions

This meta-analysis was performed to answer the following questions

related to Nigerian medicinal plants for the treatment of hypertension.

i. Would plant extracts be effective in lowering the blood pressure of

hypertensive subjects compared to control?

ii. Would plant extracts be safe as herbal remedies for hypertension?

2. Methods

2.1. Protocol

The updated Preferred Reporting Items for Systematic Reviews and

Meta-analyses (PRISMA) guidelines were followed in conducting this

systematic review (Page et al., 2021). The protocol of this study was

registered in PROSPERO with registration number: CRD42021232162.

2.2. Literature search

Cochrane, PubMed, Science Direct and Scopus databases were

searched without restriction on publication date until February 28, 2021

using the following terms: ‘Nigerian medicinal plants’ OR ‘medicinal

plants’ AND ‘hypertension’ OR ‘high blood pressure’ AND ‘humans’ OR

‘animal trials’. The eligibility studies were both clinical and preclinical

studies that utilized plants sourced from Nigerian for the treatment of

hypertension. Placebo or hypertensive subjects treated with the vehicle

or drug were the control group. A manual search of the reference list was

carried out to supplement the electronic search. Exclusion criteria were

studies that used medicinal plants not sourced from Nigeria, studies

without a comparator or the blood pressure parameters in the study

design and studies that used Nigerian medicinal plants on disease con-

ditions other than hypertension.

2.3. Outcome measures

Primary outcome measures were blood pressure (BP) parameters i.e.

systolic blood pressure (SBP) and diastolic blood pressure (DBP)

measured after the intervention. The secondary outcome measure was

the adverse event or toxicity reported during and/or after the treatment.

2.4. Data extraction and synthesis

Three independent reviewers (SAM, MAA &YS) retrieved the data

from the included studies using a predefined extraction spreadsheet and

disagreements were resolved through discussion and consensus or by a

third reviewer (ABS/AAA/MAT/JM). The details extracted from the

studies include authors’ name, year of publication, age, sex, weight, type

of plants, extraction solvent, dose, route of administration, duration of

the study, sample size, induction agent for preclinical studies, sample

size estimation and power analysis. Data for studies with more than one

dose, plant extract or model (preclinical) were combined and the

average was used for the meta-analysis. Quantitative data such as mean

and standard deviation (SD) or standard error of the mean (SEM) pre-

sented in figures were extracted using a highly magnified image soft-

ware (GetData Graph Digitizer, Version 2.26). SEM was converted to SD

using the following formula: SD = SEM ×

̅̅̅n

√ , where n is the number of

subjects.

3. Methodological quality assessment

Cochrane risk of bias tool for randomized controlled trials was used

to assess the risk of bias and was evaluated by three independent re-

viewers (SAM, YS & AH). Disagreements were resolved by consensus or

by consulting a third reviewer (MYG/AI/MB/SLP) The following do-

mains: selection bias, performance bias, detection bias, attrition bias,

reporting bias and other bias were assessed and rated as low, high or

unclear risk of bias.

3.1. Data analysis

A random-effects model was used for the meta-analysis of the pri-

mary outcome measures and heterogeneity was assessed with the I²

statistic. The mean effect size, 95% CI, forest plot and significance were

assessed using the inverse-variance method. Mean difference (MD) was

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

used for the analysis of SBP and DBP. Values of I²greater than 75% was

regarded as high heterogeneity. To evaluate the potential source of

heterogeneity and strength of the result, a subgroup and sensitivity

analysis were performed. Only groups with n ≥ 2 were included in the

subgroup analysis. Meta-analysis was performed using the Review

Manager (version 5.3), whereas Meta-Essential was used for Egger’s

regression test.

3.2. Publication bias

Publication bias was assessed using a funnel plot. Egger’s regression

asymmetry was also performed to confirm the results of the funnel plot

as previously reported (Egger et al., 1997).

4. Results

4.1. Selection of studies

A total of 1622 studies was identified from Cochrane, PubMed, Sci-

ence Direct and Scopus databases. Additional 23 studies were identified

through manual search. The full-text articles assessed for eligibility were

35. Out of 35 eligible articles, 28 (23 preclinical and 5 clinical studies)

met the inclusion criteria and were included in the review. The

remaining 7 articles were excluded due to the following reasons; Plant

not sourced from Nigeria or no detail (n=2), diabetes mellitus (n=1), not

plant extract (n=2) and no BP parameters (n=2). The description of the

search strategies is presented in Fig. 1.

4.2. Depiction of study characteristics

The characteristics of included studies showed that different plant

extracts were used for the intervention and these are depicted in Table 1.

In this systematic review, 19 out of the 28 studies that met the inclusion

criteria were enrolled for the meta-analysis involving 16 preclinical and

3 clinical studies. The total number of plants utilized were 16 from both

the animal and clinical studies.

4.3. Preclinical studies

The results of the animal studies indicated that H. sabdariffa was

reported in 4 studies (Balogun et al., 2019; Mojiminiyi et al., 2007,

2012; Onyenekwe et al., 1999), 3 studies were on Z. officinale (Akinyemi

et al., 2016a, 2016b; Tende et al., 2015), 2 studies each used

P. Americana (Imafidon and Fabian, 2010; Nwaefulu et al., 2009), C.

longa (Akinyemi et al., 2016a, 2016b), V. doniana (Ladeji et al., 1996;

Ogbeche et al., 2001), and A. sativum (Nwokocha et al., 2011; Tende

et al., 2015). M. cecropioides (Adeneye et al., 2006), B. coccineus (Akin-

dele et al., 2014), V. album (Eno et al., 2004), P. amarus (Amaechina and

Omogbai, 2007), M. flagellipes (Jovita et al., 2017), E. camaldulensis

(Nwaogu et al., 2018), N. latifolia (Nworgu et al., 2008), L. bengwensis

(Obatomi et al., 1996), P. curatellifolia (Omale et al., 2011), V. amyg-

dalina (Oyema-Iloh et al., 2018) and E. guineensis (Nkanu et al., 2019)

were each reported in 1 study. The part of the plants used for extraction

includes leaf, root, calyx, stem bark, rhizome and bulb, respectively.

Water (18 studies) was the most reported solvent that was used for the

extraction, followed by ethanol (3 studies), then methanol (2 studies)

and 1 study reported hydro-ethanol as the extraction solvent. The

duration of studies varies across the studies, ranging from a minimum of

8 days to a maximum of 18 weeks. Similarly, the dose administered to

the animals differs across the studies. The dosage range was between

0.0005 and 1000 mg/kg body weight. Different strategies were

employed in the induction of hypertension. It was observed that 8% salt,

N-nitro-L-arginine methyl ester (L-NAME) (40 and 50 mg/kg), 35%

ethanol, 7% sucrose and 15 mg of deoxycorticosterone acetate (DOCA)

were the various inducing agents used for the induction of hypertension.

Nephrectomy was also reported as the induction strategy. The summary

of study characteristics is depicted in Table 1.

4.4. Clinical studies

The results of clinical trials (Table 1) showed that the extract from

H. sabdariffa was reported in 4 (Aliyu et al., 2014; Nwachukwu et al.,

2015a, 2015b, 2017) out of the 5 studies included in this meta-analysis,

whereas P. americana was reported in 1 study (Olaniyan, 2014). Four

studies reported water as the solvent for extraction and the fifth study

adopted a crushing strategy to release the liquid from the leaf for

administration. The minimum dosage was 15 mg/kg, whereas 150

mg/kg was the maximum reported dose for the administration to the

subjects. Calyx and leaf.were the parts of the plant utilized for the

extraction of bioactive compounds.

4.5. Risk of bias assessment

The methodological rigour of the included studies was evaluated

using the Cochrane risk of bias tool for randomized controlled trials

(Higgins et al., 2011). The overall risk of bias of the included studies

ranges from moderate to high risk of bias, as most of the important

details were not reported in the included studies. It was observed that

only a few studies mentioned the randomization of subjects without

giving details. Furthermore, the allocation concealment, incomplete

outcome data, selective reporting and other risks of bias domains were

judged as low and unclear in most of the included studies because the

details required for these domains were reported. However, domains of

blinding of participants and outcome assessment were rated as high risk

of bias in almost all the included trials, as the details for these domains

were not reported. Only one study reported sample size estimation and

power analysis (Nwachukwu et al., 2015a). The risk of bias of individual

studies of preclinical and clinical trials is shown in Fig. 2a–b, whereas

the overall risk of bias of the domains assessed is depicted in Fig. 3a–b.

4.6. Systolic and diastolic pressure

4.6.1. Preclinical trials

The result of the effect of medicinal plant extract on SBP was re-

ported in 16 studies, involving 202 animals (Fig. 4a). When the hyper-

tensive animals were treated with the extract, a significant reduction in

SBP was observed in favour of the treated group with MD of −43.60

mmHg, 99% CI: −63.18, −24.01; p<0.0001. However, significant het-

erogeneity was observed across the studies (I²= 99%; p<0.00001),

Fig. 1. Flow chart of the trial search process. DM-diabetes mellitus, BP –

blood pressure.

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

suggesting there was a variation in the outcome measures between

studies. Treatment of the animals with the extract also reduced DBP

(−29.50 mmHg, 95 CI: −43.66, −15.34; p<0.0001) with substantial

heterogeneity between the studies (I²= 98%; p<0.00001). The number

of studies included in the analysis was 14 studies that utilized 81 animals

(Fig. 4b).

4.7. Clinical studies

The effects of plant extract on SBP and DBP on hypertensive subjects

are presented in Fig. 5a and b. Three studies that used extracts from

H. sabdariffa were enrolled for the meta-analysis, involving 140 subjects.

Treatment of hypertensive patients with the extract of H. sabdariffa

significantly reduced SBP compared to control subjects (−13.98 mmHg,

95 CI: −19.08, −8.88; p<0.00001) with non-significant heterogeneity

(I²= 55%; p=0.11) between the studies. Similarly, H. sabdariffa

significantly reduced DBP of hypertensive subject when compared with

control subjects (−10.00 mmHg, 95 CI: −12.22, −7.78; p<0.00001)

with homogeneity (I²= 0%; p=0.40) between studies. A subgroup

analysis was not performed for clinical studies because there was a

similarity in outcome measures between the included studies.

4.8. Adverse event

This outcome was planned a priori as the secondary outcome mea-

sure. The results showed that the plant extracts were safe as no cases of

Table 1

Characteristics of included studies.

Author & Year

Plant type & part

Solvent for

extraction

Age/weight/sex

Induction agent/specie

Dose & treatment

route

Sample

size

Duration of

the study

Preclinical studies

Adeneye et al.

(2006)

M. cecropioides/stem bark

Water/hot

10–12 wk/

150–200 g/M & F

Rat

0.0005–0.05 mg/kg/

–

Akindele et al.

(2014)

B. coccineus/leaf

Hydro-

ethanol/cold

150 g/M & F

35% ethanol & 5–7%

sucrose/rat

100,200, 400 mg/

kg/Oral

8 wk

Akinyemi et al.

(2016a)

Z. officinale.& C. longa/

rhizome

–

200–300 g/M

40 mg/kg l-NAME/rat

4% DF/oral

13 wk 3 d

Akinyemi et al.

(2016a)

Z. officinale.& C. longa/

rhizome

–

200–300 g/M

40 mg/kg l-NAME/rat

4% DF/oral

24 d

Amaechina &

Omogbai (2007)

P. amarus/leaf

Water/hot

1.2–2 kg

Rabbit

5–80 mg/kg IV

–

Anaka et al. (2009)

P. americana/seed

Water/cold

235–285 g/M

Rat

240, 260, 280 mg/

kg/oral

10 d

Balogun et al. (2019)

H. sabdariffa/leaf

Water/hot

10–12 wk/196.5

± 2.93 g/M

8% salt/rat

100, 200 & 400 mg/

kg/oral

6 wk

Eno et al. (2004)

V. album/leaf

Water/hot

200–250 g/M

15 mg/100g DOCA/rat

5–160 mg/kg/IV

6 wk

Etah et al. (2019)

E. guineensis/oil

180–250 g/M

Rat

15% oil

18 wk

Imafidon &

Amaechina (2010)

P. Americana/seed

Water/cold

–

8% salt/rat

200, 500,700 mg/kg

4 wk

Jovita et al. (2017)

M. flagellipes/seed

Ethanol/hot

100–200 g/M

Rat/8% salt +1% salt in

water

25, 50, 100 mg/kg/

oral

3 wk

Ladeji et al. (1996)

V. doniana/stem bark

Water/cold

250–300 g/F

Rat

200–800 mg/kg/oral

& IV

–

Mojiminiyi et al.

(2007)

H. sabdariffa/calyx

Water/hot

208.2±8.2 g/M

8% salt & 50 mg/kg L-

NAME/rat

1–125 mg/kg/IV

–

Mojiminiyi et al.

(2012)

H. sabdariffa/calyx

Water/hot

112–140 g

8% salt/rat

6 mg/ml

12 wk

Nwaogu et al. (2018)

E. camaldulensis/stem bark

MeOH/cold

180–250 g/M & F

8% salt/rat

50, 100, 200 mg/kg/

oral

7 wk

Nwokocha et al.

(2011)

A. sativum/bulb

Water/cold

150–180 g/5–7

wk/M

2 kidney, 1-clip model/

rat

20 mg/ml/IV

–

Nworgu et al. (2008)

N. latifolia/root

Ethanol/hot

180–250 g/M

Nephrectomy

2.5–20 mg/kg IV

–

Obatomi et al.

(1996)

L. bengwensis/leaf

Water/hot

230 g

SHR

Oral

–

8 d

Ogbeche et al.

(2001)

V. doniana/seed

Water/cold

200–250 g

SHR

200, 400, 800 mg/kg

Oral & IV

8 d

Omale et al. (2011)

P. curatellifolia/bark

Ethanol/hot

–

Cat

1 mg/ml/IV

–

Onyema-Iloh et al.

(2018)

V. amygdalina/leaf

MeOH/cold

120–160 g/M

8% salt/rat

200, 400 mg/kg/oral

8 wk

Onyenekwe et al.

(1999)

H. sabdariffa/calyx

Water/hot

–

SHR

500, 1000 mg/kg/

Oral

8 wk

Tende et al. (2015)

A. sativum & Z. officinale/

rizhome & bulb

Water/cold

12–16 wk/

150–200 g

Cat

0.1–20 mg/ml/IV

–

Clinical studies

Aliyu et al. (2014)

H. sabdariffa/calyx

Water/hot

29.9±1.6 yr/

67.3±2.7 kg

CPT/HGE (Sokoto)

15 mg/kg/oral

2 h

Nwachukwu et al.

(2015a)

H. sabdariffa/calyx

Water/hot

31–70 yr

Hypertensive patient

(Enugu)

150 mg/kg Oral

5 wk

Nwachukwu et al.

(2015b)

H. sabdariffa/calyx

Water/hot

M & F

Hypertensive patient

(Enugu)

150 mg/kg/oral

4 wk

Nwachukwu et al.

(2017)

H. sabdariffa/calyx

Water/hot

35–68 yr/M & F

Hypertensive patient

(Enugu)

150 mg/kg oral

4 wk

Olaniyan (2014)

P. Americana/leaf

Crushing

≥45 yr/M & F

Hypertensive patient

(Oke-Ogun, Oyo)

60 ml/d

–

CPT- Cold pressor test, d-day, DF-diet formulation, DOCA-deoxycorticosterone acetate, F- female, HGE-handgrip exercise, L-NAME- N-nitro-L-arginine methyl ester, M-

male, MeOH- methanol, SHR-spontaneously hypertensive rat, wk-week.

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

adverse effect was reported except one study that recorded mortality at a

higher dose of the extract (Onyenekwe et al., 1999).

4.9. Subgroup and sensitivity analyses

We performed subgroup analyses for preclinical studies to determine

the source of heterogeneity observed for the outcome measures. The

studies were stratified into plant type and duration of follow-up. For the

type of plant, the studies were subgrouped into 2 (H. sabdariffa and

Z. officinale/C. longa) (Fig. 6a). The result of SBP showed a significant

effect size with high heterogeneity between the studies (I²= 84%;

p<0.0003) for H. sabdariffa. Similarly, there was significant heteroge-

neity for DBP of H. sabdariffa subgroup (I²= 81%; p<0.001) (Fig. 6b).

Furthermore, a non-significant heterogeneity (I²= 38%; p=0.20) on the

effect of Z. officinale/C. longa on SBP was observed (Fig. 6a). However,

there was no subgroup analysis on DBP for the Z. officinale/C.longa

subgroup because of a lack of sufficient data. The results of the duration

of the follow-up subgroup, which was stratified into ≤4 and ≥ 4 weeks

showed a huge variation on both the SBP (Fig. 6c) and DBP (Fig. 6d)

parameters, suggesting this subgroup did not have an effect on the

variation observed on the outcome measures. To ascertain the robust-

ness of the estimated pooled effect size of the outcomes, we also

Fig. 2a. Risk of bias assessment in individual preclinical trials.

Fig. 2b. Risk of bias assessment in individual clinical trials.

Fig. 3a. Risk of bias item presented as percentages across the preclinical trials.

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

performed a leave-one-out analysis to determine the source of hetero-

geneity observed between the studies. This was done by continually

removing one study at a time and recalculating the effect size of the

residual studies. It was observed that the heterogeneity was not

considerably changed for both SBP and DBP, suggesting that the varia-

tions between studies were not driven by any single study.

4.10. Publication bias

The publication bias was evaluated with a funnel plot and Egger’s

regression test. Visual inspection of the funnel plots of both the SBP

(Fig. 7a) and DBP (Fig. 7b) suggest no evidence of publication bias and

this was confirmed by Egger’s regression asymmetry. Results of Egger’s

regression test also showed no evidence of publication bias for SBP

(p=0.239) and DBP (p=0.112) in animal trials. According to Sterne et al,

(2011) at least 10 studies are required to detect the real chance of

asymmetry and as such publication bias was not performed for the

clinical studies.

5. Discussion

In developing countries, a large percentage of the population relies

on herbal medicines for primary health care. The use of herbs or eth-

nobotanicals as medicinal products is not only restricted to developing

countries as the industrialized nations have also developed interests in

natural therapies (Wachtel-Galor and Benzie, 2011) because of their

relative safety. The safety and efficacy of medicinal plants have been

evaluated in several studies, ranging from animal to clinical trials.

Therefore, this meta-analysis was conceived to assess the pooled effect

size of various plants that have been tested for the treatment of hyper-

tension in Nigeria. The primary outcome measures were the SBP and

DBP measured after the intervention, whereas safety was the secondary

outcome measure.

The result showed that the treatment of hypertensive subjects with

the plant extracts significantly reduced the SBP and DBP in both animal

and clinical studies. However, substantial heterogeneity was observed in

the animal studies, whereas a low heterogeneity was observed for the

outcome measures of clinical trials. The study revealed that extract from

16 different plants were utilized for the intervention in the trials with

H. sabdariffa being the highest number of plant extract. Secondary

metabolite such as phenolic, flavonoid, alkaloid, vitamins and others are

the various bioactive compounds that are responsible for the observed

therapeutic effects of the extract. Consistent with this observation,

various studies have shown that these bioactive compounds are capable

of lowering platelet aggregation, increase endothelium nitric oxide and

decrease oxidation of low density lipoproteins that are implicated in the

pathogenesis of hypertension (Apostolidou et al., 2015; de Figueiredo

et al., 2017; Luciano et al., 2011). We are not able to summarize the

safety outcome measure of the extracts because of a lack of meaningful

data. Although one study reported mortality at a higher dose of the

extract, the overall results of the included studies showed that the plant

extracts seem not causing adverse events or toxicities. Therefore, the

results of this meta-analysis demonstrate the efficacy and safety of these

medicinal plants in lowering blood pressure, indicating they can be

harnessed for the treatment of hypertension.

The methodological quality of the included studies showed that some

key elements were not reported, especially in animal studies. This

observation could be responsible for the high heterogeneity observed in

the outcome measures of these preclinical trials. Of all the studies

included in this systematic review, only one clinical trial reported a

priori sample size and power estimation. The study design in preclinical

trials has been faced with some methodological flaws over the years, and

this poses a threat to internal validity, which substantially affects the

translation to clinical trials. Therefore, effort must be geared towards

improving preclinical experimental design with methodological rigour

that would limit the threat to internal validity for effective translation to

Fig. 3b. Risk of bias item presented as percentages across the clinical studies.

Fig. 4a. Change in systolic blood pressure after intervention with the plant

extract in animal trials.

Fig. 4b. Change in diastolic blood pressure after intervention with the plant

extract in animal trials.

Fig. 5a. Effect size of intervention on systolic blood pressure in clinical trials.

Fig. 5b. Effect size of intervention on diastolic blood pressure in clinical trials.

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

human studies.

Due to the high heterogeneity of the animal trials, we conducted

subgroup and sensitivity analyses of the outcome measures to determine

the strength of our results. The subgroup analyses of plant type and

duration of follow-up were conducted for the blood pressure. It was

observed that the overall results of subgroup analyses did not help in

detecting the source of heterogeneity. However, we did not conduct a

subgroup analysis on the dose, age and gender planned a priori due to

limited data to warrant the analysis. Similarly, a sensitivity analysis was

performed and the results indicated that the heterogeneity was not

driven by any single study.

The results of the funnel plot and Egger’s regression asymmetry in-

dicates no evidence of publication bias for the two outcome measures.

Taken together, this systematic review and meta-analysis present a

pooled effect size of the effectiveness of medicinal plant extracts in

lowering blood pressure of hypertensive subjects without any significant

adverse consequences. To the best of our knowledge, this is the first

meta-analysis of preclinical and clinical studies addressing the efficacy

of Nigerian medicinal plants for hypertension.

The positive findings of this meta-analysis should be interpreted in

light of the following limitations. First, the analysis of animal studies

had high heterogeneity between the studies and we were not able to

Fig. 6a. Preclinical subgroup of plant type on systolic blood pressure.

Fig. 6b. Preclinical subgroup of plant type on diastolic blood pressure.

Fig. 6c. Preclinical subgroup of the duration of follow-up on systolic blood pressure.

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

detect the source of the variations despite the sensitivity and subgroup

analyses. This suggests that the studies have methodological weakness.

However, the results of human studies, although, very small in number

had shown low variation for SBP and homogeneity for DBP. Another

limitation of this current meta-analysis is that the study included is

limited to plant extracts sourced from Nigeria, which may introduce

selection bias and this may limit the generalization of evidence. How-

ever, strong methodological rigour as seen largely in clinical studies may

not limit the generalization of the results as the studies can be repro-

duced. Lastly, the studies were based on the crude extracts and this may

hinder the delineation of the exact mechanism(s) of their action in

lowering the blood pressure. Nevertheless, since the crude extracts are a

combination of different bioactive compounds could be acting in a

concerted manner to target different pathways that have been impli-

cated in the pathophysiology of hypertension.

5.1. Future directions

A favourable clinical outcome was observed following intervention

with the extracts; however, more studies are required to isolate and

characterize the active ingredient(s) responsible for the BP-lowering

effect. This would allow an insight into the mechanisms of action of

the bioactive constituents present in the extracts. A large randomized

clinical trial with the extracts, particularly the H. sabdariffa that have

shown promising results in human studies would guarantee the effective

clinical acceptance of this herb for the treatment and management of

hypertension. Clinical trials should be extended to other plant extracts

with methodological rigour to assess their efficacy in the treatment of

hypertension. Furthermore, standardizing the dosage of these extracts

are important determinants for their efficacy and safe clinical applica-

tion. Considering all these would provide evidence of the therapeutic

importance of ethnobotanical to combat hypertension and other related

diseases.

6. Conclusions

Herbal therapies hold promising effects in lowering the BP of hy-

pertensive subjects. This meta-analysis provides evidence of medicinal

herbs in the treatment of hypertension. The preclinical studies had

methodological shortcomings that required improvements that would

allow standardization of these herbal preparations for effective clinical

translation to treat hypertension. Even though H. sabdariffa improved

the clinical outcome of hypertensive patients, the number of studies is

small, hence large clinical trials with longer duration of follow-up are

Fig. 6d. Preclinical subgroup of the duration of follow-up on diastolic blood pressure.

Fig. 7. Funnel plot for changes in blood pressure. (a) Systolic blood pressure (b) Diastolic blood pressure. The results suggest no evidence of publication bias for both

outcome measures.MD-mean difference, SE-standard error.

M.A. Abdulazeez et al.

Journal of Ethnopharmacology 279 (2021) 114342

necessary for effective clinical utilization of these herbal remedies for

hypertension.

Authors’ contribution

Conceptualization: SAM, MAA, YS. Fund acquisition: MAA, YS, ABS,

AAA, MAT, AH, MYG, JM. Data curation: SAM, YS. Data analysis and

interpretation: SAM, YS, MAA. Writing- original draft: SAM, YS. Writing-

review & editing: MAA, ABS, AAA, MAT, AH, MYG, AI, MB, JM, SLP.

SAM, MAA & YS screened the articles & extracted data. ABS, AAA, MAT

& JM resolved disagreement in article inclusion and data extraction.

SAM, YS & AH evaluated the risk of bias. MYG, AI, MB & SLP settled

disagreement in the risk of bias assessment. All authors read and

approved this final version of the manuscript.

Declaration of competing interest

The authors declare that they have no conflicts of interest.

Acknowledgements

This research work was supported by a grant from the Tertiary Ed-

ucation Trust Fund, Nigeria with grant number: TETFUND/DR&D/CE/

NRF/STI/30/Vol1.

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